The corpus luteum (CL) is an ovarian structure responsible for the maintenance of pregnancy in mammalian species, via the production of the steroid hormone progesterone. Corpora luteal defects contribute to reproductive abnormalities accounting for approximately 65% of reproductive failures. Abnormal luteal development results in decreased progesterone production and subsequent inability to support a developing fetus. Abnormal/underdeveloped CL's are largely attributed to aberrant angiogenesis. There are many factors known to regulate luteal angiogenesis including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2). All of these factors are produced in ovarian tissue corresponding to periods of high angiogenic activity (ovulatory follicles and CL development), and are regulated by the luteotropic hormone LH (luteinizing hormone). Of interest is the ability of LH to stimulate ovarian follicular production of leptin, a potent satiety hormone predominantly produced in adipose tissue. Leptin is an important metabolic hormone that exhibits both reproductive and angiogenic functional properties. Furthermore, leptin influences the function of VEGF and FGF-2 in non-ovarian tissues. Moreover, the fully functional form of the leptin receptor (OB-Rb) has been identified in developing luteal tissue, which implies that leptin is involved in luteal function. Moreover, preliminary data reported herein shows that leptin upregulates FGF-2 and VEGF in developing CL tissue. This discovery is novel in that numerous studies have attributed leptin's role in the ovary as a regulator in steroidogenic processes. However, leptin's regulatory ability is moderate at best. In addition to leptin's regulation of angiogenic factors, preliminary data reveals that loss of leptin's biological activity increases the frequency of abnormal luteal formation. Hence, the ability of LH to regulate leptin, leptin's ability to regulate angiogenic factors in luteal tissue, and the occurrence of abnormal CL's due to at reduction in bioavailable leptin, suggests that leptin may serve an important role in the development of the CL. Therefore, it is hypothesized that leptin is important for angiogenic processes in the developing CL. The proposed experiments are designed to test the hypothesis and begin to understand the mechanism (s) through which leptin regulates angiogenesis in developing luteal tissue.
The specific aims of the study proposed herein are to 1) determine the relevance of leptin to early luteal development in vivo, 2) determine leptin's ability to independently and directly stimulate luteal angiogenesis, and 3) determine the regulation of leptin and OB-Rb in the early developing CL. The long-term goal is to contribute to research searching for alternative treatments regarding luteal defects and subsequent infertility in women.
Ovarian corpora luteal tissue defects account for 65 % of miscarriages among women. Studying underlying mechanisms involved in the development of Luteal tissue is imperative to the development of alternative therapeutic treatments to reduce the disturbing percentage of aborted children.